Elp2 mutations perturb the epitranscriptome and lead to a complex neurodevelopmental phenotype.

Animals Autism Spectrum Disorder / genetics Disease Models, Animal Epigenesis, Genetic Grooming / physiology Humans Intellectual Disability / genetics Intracellular Signaling Peptides and Proteins / genetics Mice, Inbred C57BL Mice, Inbred DBA Mice, Knockout Mutation Neurodevelopmental Disorders / genetics Phenotype Sf9 Cells Spodoptera Transcriptome / genetics

Journal

Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555

Informations de publication

Date de publication:
11 05 2021
Historique:
received: 31 05 2020
accepted: 24 03 2021
entrez: 12 5 2021
pubmed: 13 5 2021
medline: 2 6 2021
Statut: epublish

Résumé

Intellectual disability (ID) and autism spectrum disorder (ASD) are the most common neurodevelopmental disorders and are characterized by substantial impairment in intellectual and adaptive functioning, with their genetic and molecular basis remaining largely unknown. Here, we identify biallelic variants in the gene encoding one of the Elongator complex subunits, ELP2, in patients with ID and ASD. Modelling the variants in mice recapitulates the patient features, with brain imaging and tractography analysis revealing microcephaly, loss of white matter tract integrity and an aberrant functional connectome. We show that the Elp2 mutations negatively impact the activity of the complex and its function in translation via tRNA modification. Further, we elucidate that the mutations perturb protein homeostasis leading to impaired neurogenesis, myelin loss and neurodegeneration. Collectively, our data demonstrate an unexpected role for tRNA modification in the pathogenesis of monogenic ID and ASD and define Elp2 as a key regulator of brain development.

Identifiants

DOI: 10.1038/s41467-021-22888-5 PMID: 33976153 PMC: PMC8113450
pubmed: 33976153
doi: 10.1038/s41467-021-22888-5
pii: 10.1038/s41467-021-22888-5
pmc: PMC8113450
doi:

Substances chimiques

ELP2 protein, human 0
Intracellular Signaling Peptides and Proteins 0

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

2678

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Auteurs

Marija Kojic (M)

The University of Queensland Diamantina Institute, Translational Research Institute, The University of Queensland, Brisbane, QLD, Australia.
Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD, Australia.
ORCID: 0000-0001-6437-283X

Tomasz Gawda (T)

Malopolska Centre of Biotechnology, Jagiellonian University, Krakow, Poland.
ORCID: 0000-0001-7906-0097

Monika Gaik (M)

Malopolska Centre of Biotechnology, Jagiellonian University, Krakow, Poland.

Alexander Begg (A)

Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD, Australia.

Anna Salerno-Kochan (A)

Malopolska Centre of Biotechnology, Jagiellonian University, Krakow, Poland.
Postgraduate School of Molecular Medicine, Warsaw, Poland.

Nyoman D Kurniawan (ND)

Centre for Advanced Imaging, The University of Queensland, Brisbane, QLD, Australia.

Alun Jones (A)

Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD, Australia.

Katarzyna Drożdżyk (K)

Malopolska Centre of Biotechnology, Jagiellonian University, Krakow, Poland.

Anna Kościelniak (A)

Malopolska Centre of Biotechnology, Jagiellonian University, Krakow, Poland.

Andrzej Chramiec-Głąbik (A)

Malopolska Centre of Biotechnology, Jagiellonian University, Krakow, Poland.

Soroor Hediyeh-Zadeh (S)

Bioinformatics Division, Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia.
Department of Medical Biology, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Melbourne, VIC, Australia.
ORCID: 0000-0001-7513-6779

Maria Kasherman (M)

School of Biomedical Sciences, The University of Queensland, Brisbane, QLD, Australia.

Woo Jun Shim (WJ)

Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD, Australia.
School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, QLD, Australia.
ORCID: 0000-0001-9446-7821

Enakshi Sinniah (E)

Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD, Australia.
ORCID: 0000-0002-3403-3658

Laura A Genovesi (LA)

The University of Queensland Diamantina Institute, Translational Research Institute, The University of Queensland, Brisbane, QLD, Australia.
Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD, Australia.

Rannvá K Abrahamsen (RK)

Department of Epilepsy Genetics and Personalized Medicine, Danish Epilepsy Centre, Dianalund, Denmark.
ORCID: 0000-0001-8742-783X

Christina D Fenger (CD)

Department of Epilepsy Genetics and Personalized Medicine, Danish Epilepsy Centre, Dianalund, Denmark.

Camilla G Madsen (CG)

Centre for Functional and Diagnostic Imaging and Research, Hvidovre Hospital, Hvidovre, Denmark.

Julie S Cohen (JS)

Department of Neurology and Developmental Medicine, Division of Neurogenetics, Kennedy Krieger Institute, Baltimore, MD, USA.
Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
ORCID: 0000-0003-1545-0293

Ali Fatemi (A)

Department of Neurology and Developmental Medicine, Division of Neurogenetics, Kennedy Krieger Institute, Baltimore, MD, USA.
Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
ORCID: 0000-0003-4116-6990

Zornitza Stark (Z)

Department of Paediatrics, The University of Melbourne, Melbourne, VIC, Australia.
Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Melbourne, VIC, Australia.
Australian Genomics Health Alliance, Parkville, VIC, Australia.
ORCID: 0000-0001-8640-1371

Sebastian Lunke (S)

Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Melbourne, VIC, Australia.
Australian Genomics Health Alliance, Parkville, VIC, Australia.
The University of Melbourne, Melbourne, VIC, Australia.

Joy Lee (J)

Department of Paediatrics, The University of Melbourne, Melbourne, VIC, Australia.
Department of Metabolic Medicine, Royal Children's Hospital, Parkville, VIC, Australia.

Jonas K Hansen (JK)

Department of Paediatrics, Regional Hospital Viborg, Viborg, Denmark.

Martin F Boxill (MF)

Department of Paediatrics, Regional Hospital Viborg, Viborg, Denmark.

Boris Keren (B)

Department of Genetics, Pitié-Salpêtrière Hospital, AP-HP, Paris, France.

Isabelle Marey (I)

Department of Genetics, Pitié-Salpêtrière Hospital, AP-HP, Paris, France.

Margarita S Saenz (MS)

The University of Colorado Anschutz, Children's Hospital Colorado, Aurora, CO, USA.

Kathleen Brown (K)

The University of Colorado Anschutz, Children's Hospital Colorado, Aurora, CO, USA.

Suzanne A Alexander (SA)

Queensland Brain Institute, The University of Queensland, Brisbane, QLD, Australia.
Queensland Centre for Mental Health Research, The Park Centre for Mental Health, Brisbane, QLD, Australia.

Sergey Mureev (S)

CSIRO-QUT Synthetic Biology Alliance, Centre for Tropical Crops and Bio-commodities, Queensland University of Technology, Brisbane, QLD, Australia.

Alina Batzilla (A)

Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD, Australia.
The Ruprecht Karl University of Heidelberg, Heidelberg, Germany.
ORCID: 0000-0003-3893-8355

Melissa J Davis (MJ)

Bioinformatics Division, Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia.
Department of Medical Biology, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Melbourne, VIC, Australia.
Department of Clinical Pathology, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Melbourne, VIC, Australia.
ORCID: 0000-0003-4864-7033

Michael Piper (M)

School of Biomedical Sciences, The University of Queensland, Brisbane, QLD, Australia.

Mikael Bodén (M)

School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, QLD, Australia.
ORCID: 0000-0003-3548-268X

Thomas H J Burne (THJ)

Queensland Brain Institute, The University of Queensland, Brisbane, QLD, Australia.
Queensland Centre for Mental Health Research, The Park Centre for Mental Health, Brisbane, QLD, Australia.
ORCID: 0000-0003-3502-9789

Nathan J Palpant (NJ)

Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD, Australia.
ORCID: 0000-0002-9334-8107

Rikke S Møller (RS)

Department of Epilepsy Genetics and Personalized Medicine, Danish Epilepsy Centre, Dianalund, Denmark.
Department for Regional Health Research, The University of Southern Denmark, Odense, Denmark.

Sebastian Glatt (S)

Malopolska Centre of Biotechnology, Jagiellonian University, Krakow, Poland. sebastian.glatt@uj.edu.pl.
ORCID: 0000-0003-2815-7133

Brandon J Wainwright (BJ)

The University of Queensland Diamantina Institute, Translational Research Institute, The University of Queensland, Brisbane, QLD, Australia. b.wainwright@uq.edu.au.
Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD, Australia. b.wainwright@uq.edu.au.
ORCID: 0000-0003-0406-2092

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Classifications MeSH

questionsmedicales.fr › Eucaryotes › Animaux › Elp2 mutations perturb the epitranscriptome...
questionsmedicales.fr › Troubles mentaux › Troubles du développement neurologique › Troubles généralisés du développement de l'enfant › Trouble du spectre autistique › Elp2 mutations perturb the epitranscriptome...
questionsmedicales.fr › Techniques d'investigation › Modèles théoriques › Modèles biologiques › Modèles animaux de maladie humaine › Elp2 mutations perturb the epitranscriptome...
questionsmedicales.fr › Phénomènes génétiques › Régulation de l'expression des gènes › Épigenèse génétique › Elp2 mutations perturb the epitranscriptome...
questionsmedicales.fr › Comportement et mécanismes comportementaux › Comportement › Comportement animal › Comportement appétitif › Soins du pelage › Elp2 mutations perturb the epitranscriptome...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Elp2 mutations perturb the epitranscriptome...
questionsmedicales.fr › Troubles mentaux › Troubles du développement neurologique › Déficience intellectuelle › Elp2 mutations perturb the epitranscriptome...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines et peptides de signalisation intracellulaire › Elp2 mutations perturb the epitranscriptome...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › Lignées consanguines de souris › Souris de lignée C57BL › Elp2 mutations perturb the epitranscriptome...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › Lignées consanguines de souris › Souris de lignée DBA › Elp2 mutations perturb the epitranscriptome...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › Souris transgéniques › Souris knockout › Elp2 mutations perturb the epitranscriptome...
questionsmedicales.fr › Phénomènes génétiques › Variation génétique › Mutation › Elp2 mutations perturb the epitranscriptome...
questionsmedicales.fr › Troubles mentaux › Troubles du développement neurologique › Elp2 mutations perturb the epitranscriptome...
questionsmedicales.fr › Phénomènes génétiques › Phénotype › Elp2 mutations perturb the epitranscriptome...
questionsmedicales.fr › Cellules › Cellules cultivées › Lignée cellulaire › Cellules Sf9 › Elp2 mutations perturb the epitranscriptome...
questionsmedicales.fr › Eucaryotes › Animaux › Invertébrés › Arthropodes › Insectes › Pterygota › Neoptera › Holometabola › Lepidoptera › Papillons de nuit › Spodoptera › Elp2 mutations perturb the epitranscriptome...
questionsmedicales.fr › Phénomènes génétiques › Structures génétiques › Transcriptome › Elp2 mutations perturb the epitranscriptome...